Pyrrolidine Products Research Articles

Exploring azomethine ylides reactivity with acrolein through cycloaddition reaction and computational antiviral activity assessment against hepatitis C virus.

The regioselectivity and diastereoselectivity of the 1,3-dipolar cycloaddition reaction between azomethine ylides and acrolein were investigated. The DFT studies revealed that the favored pathway leads to the formation of cis-cycloadduct pyrrolidine and these computational findings align with experimental observations. The cis-cycloadduct pyrrolidine product serves as an advanced intermediate in the synthesis of a hepatitis C virus inhibitor. For this, the antiviral activity of cis-cycloadduct pyrrolidine against cyclophilin A, the co-factor responsible for hepatitis C virus, was also evaluated through molecular docking simulations which revealed intriguing interactions and a high C-score, which were further confirmed by molecular dynamics simulations, demonstrating stability over a 100-ns simulation period. Furthermore, the cis-cycloadduct pyrrolidine exhibits favorable drug-like properties and a better ADMET profile compared to hepatitis C virus inhibitor. Chemical reactivity studies were performed using DFT method by the functional B3LYP at 6-31G (d, p) computational level by GAUSSIAN 16 program. Frontal molecular orbitals theory used to investigate HOMO/LUMO interactions between azomethine ylides and acrolein. Findings of this approach were confirmed by global reactivity indices and electron displacement was investigated based on Fukui functions. Furthermore, the activation energies were determined after frequency calculations using TS Berny algorithm and transition states were confirmed by the presence of a single imaginary frequency. Moreover, antiviral activity of cis-cycloadduct was explored through molecular docking using Surflex-Dock suite SYBYL X 2.0, and molecular dynamics simulation using GROMACS program. Finally, drug-like properties were investigated with SwissADME and ADMETlab 2.0.

Organocatalytic Asymmetric Domino [3+2]-Cycloaddition-Acyl Transfer Reaction between Azomethine Ylides and α-Nitro-α,β-Unsaturated Ketones.

Here in we have developed an organocatalytic asymmetric domino [3+2]-cycloaddition-acyl transfer reaction between in situ generated azomethine ylides and α-nitro-α,β-unsaturated ketones. The desired penta-substituted pyrrolidine products were obtained in high yields and in moderate to good enantio- and diastereoselectivities. Also, an isomerization reaction in silica gel was performed for the formation of another diastereomer in high yields with retention of enantioselectivities.

Theoretical study of nickel-catalyzed hydroalkylation of 3-pyrrolines: Origin of ligand-controlled regioselectivity

Nickel catalysts have shown unique ligand control of regioselectivity in the hydroalkylation of 3-pyrrolines. The (2-(5-bromopyridin-2-yl)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole) ligand (L1) produces a C2-alkylated pyrrolidine, while the (4-benzyl-2-(6-methylpyridin-2-yl)-4,5-dihydrooxazole) ligand (L2) delivers a C3-alkylated pyrrolidine. We have explored the mechanism and origin of the ligand-controlled regioselectivity with density functional theory (DFT) calculations. The calculation results show good agreement with the experimental results for the regioselectivity. The hydroalkylation reactions of 3-pyrrolines with the two different ligands occur via completely different mechanisms, neither of which is via the traditional route proposed by experimental research. These mechanistic rationales are supported by several related experimental observations in ref. 40. For the L1 ligand, the regioselectivity is determined by two competing transition states, a β-hydride elimination transition state and a C–C reductive elimination transition state. For the L2 ligand, radical coupling and β-H elimination steps are responsible for the regioselectivity. The bulky L1 ligand facilitates the β-hydride elimination step and thus leads to the C2-alkylated pyrrolidine product. The less bulky L2 ligand prefers radical coupling step and thus results in the C3-alkylated pyrrolidine product.

Regulating the electronic and spin structure of endohedral metallofullerenes: a case investigation of Sc3N@C80 and Sc3C2@C80.

The electrochemical and paramagnetic properties of endohedral metallofullerenes (EMFs) have drawn extensive attention due to their huge potential in the fields of molecular devices, biomedicines, quantum information processing, etc. Exohedral modification of the fullerene carbon cage, such as in the classical Prato reaction, is an effective and facile approach to regulate the electronic structure and molecular dynamics of EMFs. In this work, novel pyrrolidine products of Sc3N@C80 and Sc3C2@C80 were successfully synthesized via Prato reactions using L-cysteine and paraformaldehyde. Structure characterizations demonstrated that two regioisomers with a [5,6] and a [6,6] cycloaddition on the Ih-C80 cage were obtained both for Sc3N@C80 and Sc3C2@C80. Besides, the [6,6]-monoadduct of Sc3N@C80 was thermally stable while the [5,6]-monoadduct exhibited a retro-cycloaddition ability to recover the pristine Sc3N@C80. Electrochemical measurements revealed that the redox potential of Sc3N@C80 could be tuned via such exohedral modifications. Furthermore, the paramagnetic property and internal dynamics of the encapsulated Sc3C2 cluster of Sc3C2@C80 can be well-regulated by controlling the spin density of the molecule. The present work could provide a new approach to regulate the electronic and/or spin structure of EMFs.

Interrupted Curtius Rearrangements of Quaternary Proline Derivatives: A Flow Route to Acyclic Ketones and Unsaturated Pyrrolidines.

Conversion of N-Boc-protected quaternary proline derivatives under thermal Curtius rearrangement conditions was found to afford a series of ring-opened ketone and unsaturated pyrrolidine products instead of the expected carbamate species. The nature of the substituent on the quaternary carbon thereby governs the product outcome due to the stability of a postulated N-acyliminium species. A continuous flow process with in-line scavenging was furthermore developed to streamline this transformation and safely create products on a gram scale.

PhI(OAc)2-Mediated Dihalogenative Cyclization of 1,6-Enyne with Lithium Halide.

The dihalogenative cyclization of 1,6-enyne with the assistance of PhI(OAc)2 and lithium halide is presented. A plausible radical mechanism is proposed, which consists of addition of halogen radical to alkene, 5-exo-dig radical cyclization of enyne and halogenation via radical coupling. The alkenyl- and alkyl-halide groups in the resulted pyrrolidine products have been demonstrated to be facile handles for further transformations.

Sequential nucleophilic addition/1,2-rearrangement of N-iminolactam: A ring-contractive strategy for the synthesis of 2-acyl pyrrolidines

A sequential nucleophilic addition/ring contraction of α-bromo N-iminolactam with organometallic reagents for the synthesis of 2-acyl pyrrolidines has been developed. The reaction allows facial construction of 2-acyl pyrrolidines incorporating not only aryl and heteroaryl groups, but alkenyl, alkynyl, and alkyl groups. Moreover, 2-acyl pyrrolidine products can be further transformed into the pyrrolidinyl alcohol, epoxide, β-lactam, and pyrazole.

Enantioselective C-H Amination Catalyzed by Nickel Iminyl Complexes Supported by Anionic Bisoxazoline (BOX) Ligands.

The trityl-substituted bisoxazoline (TrHBOX) was prepared as a chiral analogue to a previously reported nickel dipyrrin system capable of ring-closing amination catalysis. Ligand metalation with divalent NiI2(py)4 followed by potassium graphite reduction afforded the monovalent (TrHBOX)Ni(py) (4). Slow addition of 1.4 equiv of a benzene solution of 1-adamantylazide to 4 generated the tetrazido (TrHBOX)Ni(κ2-N4Ad2) (5) and terminal iminyl adduct (TrHBOX)Ni(NAd) (6). Investigation of 6 via single-crystal X-ray crystallography, NMR and EPR spectroscopies, and computations revealed a Ni(II)-iminyl radical formulation, similar to its dipyrrinato congener. Complex 4 exhibits enantioselective intramolecular C-H bond amination to afford N-heterocyclic products from 4-aryl-2-methyl-2-azidopentanes. Catalytic C-H amination occurs under mild conditions (5 mol % catalyst, 60 °C) and provides pyrrolidine products in decent yield (29%-87%) with moderate ee (up to 73%). Substrates with a 3,5-dialkyl substitution on the 4-aryl position maximized the observed enantioselectivity. Kinetic studies to probe the reaction mechanism were conducted using 1H and 19F NMR spectroscopies. A small, intermolecular kinetic isotope effect (1.35 ± 0.03) suggests an H-atom abstraction step with an asymmetric transition state while the reaction rate is measured to be first order in catalyst and zeroth order in substrate concentrations. Enantiospecific deuterium labeling studies show that the enantioselectivity is dictated by both the H-atom abstraction and radical recombination steps due to the comparable rate between radical rotation and C-N bond formation. Furthermore, the competing elements of the two-step reaction where H-removal from the pro-R configuration is preferred while the preferential radical capture occurs with the Si face of the carboradical likely lead to the diminished ee observed, as corroborated by theoretical calculations. Based on these enantio-determining steps, catalytic enantioselective synthesis of 2,5-bis-tertiary pyrrolidines is demonstrated with good yield (50-78%) and moderate ee (up to 79%).

C–H Amination Mediated by Cobalt Organoazide Adducts and the Corresponding Cobalt Nitrenoid Intermediates

Treatment of (ArL)CoBr (ArL = 5-mesityl-1,9-(2,4,6-Ph3C6H2)dipyrrin) with a stoichiometric amount of 1-azido-4-(tert-butyl)benzene N3(C6H4-p-tBu) furnished the corresponding four-coordinate organoazide-bound complex (ArL)CoBr(N3(C6H4-p-tBu)). Spectroscopic and structural characterization of the complex indicated redox innocent ligation of the organoazide. Slow expulsion of dinitrogen (N2) was observed at room temperature to afford a ligand functionalized product via a [3 + 2] annulation, which can be mediated by a high-valent nitrene intermediate such as a CoIII iminyl (ArL)CoBr(•N(C6H4-p-tBu)) or CoIV imido (ArL)CoBr(N(C6H4-p-tBu)) complex. The presence of the proposed intermediate and its viability as a nitrene group transfer reagent are supported by intermolecular C-H amination and aziridination reactivities. Unlike (ArL)CoBr(N3(C6H4-p-tBu)), a series of alkyl azide-bound CoII analogues expel N2 only above 60 °C, affording paramagnetic intermediates that convert to the corresponding Co-imine complexes via α-H-atom abstraction. The corresponding N2-released structures were observed via single-crystal-to-crystal transformation, suggesting formation of a Co-nitrenoid intermediate in solid-state. Alternatively, the alkyl azide-bound congeners supported by a more sterically accessible dipyrrinato scaffold tBuL (tBuL = 5-mesityl-(1,9-di-tert-butyl)dipyrrin) facilitate intramolecular 1,3-dipolar cycloaddition as well as C-H amination to furnish 1,2,3-dihydrotriazole and substituted pyrrolidine products, respectively. For the C-H amination, we observe that the temperature required for azide activation varies depending on the presence of weak C-H bonds, suggesting that the alkyl azide adducts serve as viable species for C-H amination when the C-H bonds are (1) proximal to the azide moiety and (2) sufficiently weak to be activated.

Catalytic (3+2) Palladium‐Aminoallyl Cycloaddition with Conjugated Dienes

AbstractWe describe the design and application of tailored aminoallyl precursors for catalytic (3+2) cycloaddition with conjugated dienes via a Pd‐aminoallyl intermediate. The new cycloaddition reactions override the conventional (4+3) selectivity of aminoallyl cation cycloaddition through a sequence of Pd‐allyl transfer and ring closure. A variety of highly substituted or fused pyrrolidine rings were synthesized using the cycloaddition, and can further undergo [1,3] N‐to‐C rearrangement to five‐membered carbocycles with a different palladium catalyst. The utility of the (3+2) cycloaddition is also demonstrated by the preparation of various derivatives from the bicyclic pyrrolidine products.

Catalytic (3+2) Palladium-Aminoallyl Cycloaddition with Conjugated Dienes.

We describe the design and application of tailored aminoallyl precursors for catalytic (3+2) cycloaddition with conjugated dienes via a Pd-aminoallyl intermediate. The new cycloaddition reactions override the conventional (4+3) selectivity of aminoallyl cation cycloaddition through a sequence of Pd-allyl transfer and ring closure. A variety of highly substituted or fused pyrrolidine rings were synthesized using the cycloaddition, and can further undergo [1,3] N-to-C rearrangement to five-membered carbocycles with a different palladium catalyst. The utility of the (3+2) cycloaddition is also demonstrated by the preparation of various derivatives from the bicyclic pyrrolidine products.

Synthesis of Chlorotrifluoromethylated Pyrrolidines by Electrocatalytic Radical Ene-Yne Cyclization.

The stereoselective synthesis of chlorotrifluoromethylated pyrrolidines was achieved using anodically coupled electrolysis, an electrochemical process that combines two parallel oxidative events in a convergent and productive manner. The bench-stable and commercially available solids CF3 SO2 Na and MgCl2 were used as the functional group sources to generate CF3. and Cl. , respectively, via electrochemical oxidation, and the subsequent reaction of these radicals with the 1,6-enyne substrate was controlled with an earth-abundant Mn catalyst. In particular, the introduction of a chelating ligand allowed for the ene-yne cyclization to take place with high stereochemical control over the geometry of the alkene group in the pyrrolidine product.

Intramolecular Aminoalkoxylation of Unfunctionalized Olefins via Intramolecular Iodoamination and Aziridinium Ion Ring-Opening Sequence.

The preparation of prolinol ether type compounds was realized via MnI2-catalyzed intramolecular iodoamination of unfunctionalized olefins and subsequent ring opening of an aziridinium ion intermediate with alcohols/phenols. In the presence of a catalytic amount of MnI2 and 2 equiv of NaI, intramolecular aminoalkoxylation of different N-benzyl-5-methylhex-4-en-1-amine substrates proceeded readily in alcoholic solvents, leading to 2-(alkoxyalkyl)pyrrolidine products in up to 90% isolated yields.

Intramolecular [2 + 2] and [4 + 2] Cycloaddition Reactions of Cinnamylamides of Ethenetricarboxylate in Sequential Processes.

Intramolecular [2 + 2] and [4 + 2] cycloaddition reactions of cinnamylamides of ethenetricarboxylate in sequential processes have been studied. Reaction of 1,1-diethyl 2-hydrogen ethenetricarboxylate and trans-cinnamylamines in the presence of EDCI/HOBt/Et3N led to pyrrolidine products in one pot, via intramolecular [2 + 2], [4 + 2], and some other cyclizations. The types of the products depend on the substituents on the benzene ring and the reaction conditions. Reaction of cinnamylamines without substituents on the benzene ring and with halogens and OMe on the para position at room temperature gave cyclobutane-fused pyrrolidines as major products via [2 + 2] cycloaddition. The reaction at 80 °C in 1,2-dichloroethane gave δ-lactone fused pyrrolidines as major products, probably via ring-opening of the cyclobutanes. Interestingly, reaction of 1,1-diethyl 2-hydrogen ethenetricarboxylate and cinnamylamines bearing electron-withdrawing groups such as NO2, CN, CO2Me, CO2Et, and CF3 on ortho and para positions in the presence of EDCI/HOBt/Et3N at room temperature or at 60-80 °C gave tetrahydrobenz[f]isoindolines via [4 + 2] cycloaddition as major products. DFT studies have been performed to explained the observed [2 + 2]/[4 + 2] selectivity.

Palladium‐catalyzed highly selective intramolecular bromoamination of alkenes: Efficient synthesis of substituted pyrrolidines

A new method has been developed for the preparation of substituted pyrrolidines by the palladium‐catalyzed intramolecular bromoamination of substituted aminoalkenes. The catalytic system and reaction conditions used for this transformation have been fully optimized. Notably, this reaction exhibits excellent selectivity, affording the pyrrolidine products as single 5‐exo‐bromoalkylpyrrolidines in excellent yields. Furthermore, this reaction occurs at room temperature under mild conditions, reaching completion within 1 h.

ChemInform Abstract: Synthesis of Highly Functionalized Chiral Benzopyrano[3,4‐c]pyrrolidines Bearing Five Contiguous Stereogenic Centers.

A chiral bis(imidazolidine)pyridine-Cu complex smoothly catalyzed the asymmetric [3 + 2] cycloaddition reaction of α,β-unsaturated ester-containing nitroalkenes with imino esters to give endo-pyrrolidine products in a highly enantioselective manner while maintaining the α,β-unsaturated ester functionality. Subsequent intramolecular diastereoselective cyclizations of the obtained pyrrolidine products were accomplished by treatment with KF/Al2O3 in toluene/EtOH (4:1) to give highly functionalized benzopyrano[3,4-c]pyrrolidines bearing five contiguous stereogenic centers.

Synthesis of Highly Functionalized Chiral Benzopyrano[3,4-c]pyrrolidines Bearing Five Contiguous Stereogenic Centers.

A chiral bis(imidazolidine)pyridine-Cu complex smoothly catalyzed the asymmetric [3 + 2] cycloaddition reaction of α,β-unsaturated ester-containing nitroalkenes with imino esters to give endo-pyrrolidine products in a highly enantioselective manner while maintaining the α,β-unsaturated ester functionality. Subsequent intramolecular diastereoselective cyclizations of the obtained pyrrolidine products were accomplished by treatment with KF/Al2O3 in toluene/EtOH (4:1) to give highly functionalized benzopyrano[3,4-c]pyrrolidines bearing five contiguous stereogenic centers.

Synthesis of Tetrahydro‐1,2‐oxazines and Pyrrolidines via Cycloadditions of Donor–Acceptor Cyclobutanes and Nitrosoarenes

AbstractDuring efforts to expand the scope of Lewis‐acid‐catalyzed [4+2] cycloaddition between donor–acceptor cyclobutanes and nitrosoarenes, an unexpected formation of pyrrolidine products was discovered when 50 mol‐% of MgI2 was used as a Lewis acid. It was also observed that the electronics of the nitrosoarene and judicious selection of the Lewis acid catalyst have a profound effect on the regioselectivity of the reaction.

Allylic aminations with hindered secondary amine nucleophiles catalyzed by heterobimetallic Pd-Ti complexes.

Phosphinoamide-scaffolded heterobimetallic palladium-titanium complexes are highly effective catalysts for allylic aminations of allylic chlorides with hindered secondary amine nucleophiles. Three titanium-containing ligands are shown to assemble active catalysts in situ and enable catalysis at room temperature. A variety of sterically bulky secondary amines are efficiently allylated in high yields with as little as 1 mol % palladium catalyst. Piperidine and pyrrolidine products are also efficiently generated via intramolecular aminations with hindered amine nucleophiles.

ChemInform Abstract: One‐Pot Tandem Strecker Reaction and Iminocyclisations: Syntheses of Trihydroxypiperidine α‐Iminonitriles.

Unbranched, and α- and β-methyl-branched, trihydroxypiperidine α-iminonitriles have been obtained in a single step from protected 5-O-tosylate pentoses. This reaction comprises a one-pot tandem Strecker reaction and iminocyclisation. These trihydroxypiperidine α-iminonitriles are precursors to trihydroxypipecolic acids. No formation of pyrrolidine products was observed.